Factors that modulate cellular homeostasis to overcome replicative stress in aging

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We have examined the activity of different compounds on the frequency of single replication forks stalled at a strong block. Some recent results are summarized here: We have found that inhibitors of poly ADP ribose synthesis, which are used in cancer therapy, increase the frequency of single fork stalling. In contrast, inhibition of the degradation of poly ADP ribose reduces the frequency of single stalled forks. A compound that enhances the activity of a protein chaperone that improves correct protein folding also reduces the frequency of single fork stalling events. Our results suggest that some small molecule effectors can influence events at the level of the genome, such that the frequency of a genome destabilizing and stress inducing event is reduced. We plan to test additional compounds, and will follow those that show activity in the assay. We have also shown that assay can be performed in murine hematopoietic stem cells (HSCs). This makes it possible to examine the influence of "anti aging" compounds on the competence of stem cells, from young and old donors, to resist replication stress. We find that the frequency of single fork stalling events rises in HSCs from old as compared to young donors. Furthermore, we have examined the age at which the increase in single fork stalling events can be observed. Remarkably this appears at an equivalent to middle age in mice. Consequently it appears that in this mouse stem cell model cellular competence to overcome replication blocks declines well before they reach an "aged" status.